p53 is regulated by aerobic glycolysis in cancer cells by the CtBP family of NADH-dependent transcriptional regulators

High rates of glycolysis in cancer cells are a well-established characteristic of many human tumors, providing rapidly proliferating cancer cells with metabolites that can be used as precursors for anabolic pathways. Maintenance of high glycolytic rates depends on the lactate dehydrogenase-catalyzed...

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Veröffentlicht in:Science signaling 2020-05, Vol.13 (630)
Hauptverfasser: Birts, Charles N, Banerjee, Arindam, Darley, Matthew, Dunlop, Charles R, Nelson, Sarah, Nijjar, Sharandip K, Parker, Rachel, West, Jonathan, Tavassoli, Ali, Rose-Zerilli, Matthew J J, Blaydes, Jeremy P
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Sprache:eng
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Zusammenfassung:High rates of glycolysis in cancer cells are a well-established characteristic of many human tumors, providing rapidly proliferating cancer cells with metabolites that can be used as precursors for anabolic pathways. Maintenance of high glycolytic rates depends on the lactate dehydrogenase-catalyzed regeneration of NAD from GAPDH-generated NADH because an increased NADH:NAD ratio inhibits GAPDH. Here, using human breast cancer cell models, we identified a pathway in which changes in the extramitochondrial-free NADH:NAD ratio signaled through the CtBP family of NADH-sensitive transcriptional regulators to control the abundance and activity of p53. NADH-free forms of CtBPs cooperated with the p53-binding partner HDM2 to suppress p53 function, and loss of these forms in highly glycolytic cells resulted in p53 accumulation. We propose that this pathway represents a "glycolytic stress response" in which the initiation of a protective p53 response by an increased NADH:NAD ratio enables cells to avoid cellular damage caused by mismatches between metabolic supply and demand.
ISSN:1945-0877
1937-9145
DOI:10.1126/scisignal.aau9529